Primary biliary cirrhosis (PBC) is an autoimmune disease of unknown etiology characterized by slowly progressive intrahepatic cholestasis due to non-suppurative inflammatory destruction of small intrahepatic bile ducts. Because some other autoimmune diseases appear to respond favorably to certain immunosuppressive agents, trials of selected immunosuppressive drugs are being undertaken in patients with PBC. In a randomized controlled trial of chlorambucil therapy, treatment with the drug was associated with a decrease in the rate of increase of serum bilirubin, normalization of elevated serum IgM levels and an improvement in inflammatory cell infiltration in liver biopsies. These encouraging findings have prompted a search for safer and more effective immunosuppressive drugs with less carcinogenic potential than chlorambucil. One promising drug of this type is methotrexate. Ten patients with symptomatic PBC were admitted to an open trial of low-dose (15 mg) once weekly oral methotrexate. Two patients with advanced (stage III-IV) disease dropped out after 4-5 months. The remaining 7 were followed for 8- 24 months. Methotrexate therapy in these patients was associated with significant decreases in elevated serum levels of IgM and alkaline phosphatase and a more than 50% decrease in symptom scores for fatigue and pruritus. Serum ALT levels initially increased (4 and 8 mo.) but subsequently fell to 10% below baseline. In 4 patients, who had liver biopsies before and after one year of treatment, methotrexate was prompted the initiation of a randomized trial of two doses of methotrexate (7.5 and 15 mg/week) for asymptomatic as well as symptomatic patients with PBC.